Difficulty: Intermediate to Advanced | Prerequisites: Part 1 of these notes (functional groups, alkyl halide web, alkynides), SN1/SN2/E1/E2 mechanisms
This part covers how to plan and execute multi-step syntheses: choosing intermediates, converting leaving groups, working backwards from a target (retrosynthesis), and evaluating whether a route can be made more efficient. The four-question framework (what changed? how do I make that group? what can my starting material do? what mechanism applies?) is the systematic approach for tackling any synthesis problem on an exam.
Synthetic intermediate
A compound produced in one step of a synthesis that serves as the starting material for the next step. Think of it as a stepping stone between your starting material and your target.
Retrosynthetic analysis
The strategy of working backwards from the target compound, mentally "disconnecting" bonds to identify what precursors and reagents would be needed. In simple terms, you start with the answer and figure out the question.
Synthetic efficiency
A measure of how few steps and how little wasted material a route requires. A more efficient synthesis uses fewer steps, avoids unnecessary intermediates, and maximises the yield at each stage.
Tosylate (OTs)
A sulfonate ester leaving group installed by treating an alcohol with tosyl chloride (TsCl) and pyridine. Think of it as converting a bad leaving group (-OH) into an excellent one (-OTs) without changing the carbon skeleton or the stereochemistry at that carbon.
Leaving group conversion
The process of converting a functional group that cannot leave (such as -OH) into one that can (such as -Br, -Cl, or -OTs). Common reagents include PBr₃/pyridine, SOCl₂/pyridine, and TsCl/pyridine.
Stereochemical inversion (Walden inversion)
The flip in configuration at a carbon centre that occurs during an SN2 reaction due to backside attack. Each SN2 step inverts once; two sequential SN2 reactions on the same centre restore the original configuration (double inversion = retention).
Finkelstein reaction
A halide exchange reaction where one alkyl halide is converted to another (typically R-Br or R-Cl to R-I) using NaI, often driven by the precipitation of NaBr or NaCl in acetone.
When you face a synthesis problem, work through these questions systematically:
What is changing from reactant to product? Identify new bonds formed in the target, atoms added to the starting material, key regiochemical relationships, and map the atoms of the starting material onto the target.
How do I make the functional group present in the product? Think about which reactions install that group.
What reactions can the reactant undergo? Consider what the starting material's functional group allows.
Consider reaction mechanisms. Will SN1, SN2, E1, or E2 dominate given the substrate, nucleophile/base, and solvent?
You can work forward (from starting material) or backward (from target). Often the best approach is to do both and meet in the middle.
The general format for a two-step synthesis:
Reactant → (Reagents, Reaction 1) → Intermediate → (Reagents, Reaction 2) → Target
The product of reaction 1 is the starting material for reaction 2. Choosing the right intermediate is the core skill.
Worked example from the worksheet (Q5):
Starting material: an alkene. Target: an alkyl bromide (with Markovnikov regiochemistry).
Step 1 (addition): H₃O⁺ (or H₂SO₄/H₂O) adds water across the double bond to give a Markovnikov alcohol (the intermediate).
Step 2 (leaving group installation): HBr, or PBr₃/pyridine, or TsCl/pyridine followed by NaBr/DMSO, converts the alcohol to the alkyl bromide.
Making it more efficient: The entire two-step sequence can be replaced by a single step: direct addition of HBr to the alkene gives the Markovnikov alkyl bromide in one step. Always ask whether a shorter route exists.
Vildagliptin is a type 2 diabetes drug. The worksheet focuses on the nitrile-bearing pyrrolidine portion of its structure.
The retrosynthetic question: how do you install a -CN group with the correct stereochemistry?
The electrophile is identified as the pyrrolidine ring bearing a bromine with a specific stereochemistry (the leaving group).
The nucleophile is cyanide (CN⁻).
The reaction is SN2, which means backside attack and inversion of configuration. The bromine must be on the opposite face from where you want the CN to end up.
This is a direct application of the alkyl halide reaction web: R-X + NaCN → R-CN.
The worksheet asks for two different synthetic routes to each target, each with at least two steps. Here are the key patterns:
Converting an alcohol to a different functional group:
Alcohol → tosylate (TsCl, pyridine) → then SN2 with a nucleophile
Alcohol → alkyl halide (PBr₃/pyr, or SOCl₂/pyr) → then SN2 or E2
Alcohol → alkene (H₂SO₄, heat) → then further reactions
Converting an alkene to a different functional group:
Alkene → alcohol (hydroboration-oxidation or acid-catalysed hydration) → then leaving group installation → then SN2
Alkene → alkyl halide (HBr or HCl) → then SN2 with nucleophile
Building C-C bonds:
Install a leaving group on a primary substrate → react with NaC≡CH (alkynide) for SN2 to form a new C-C bond
Install a leaving group → react with NaCN for SN2 to add one carbon with a nitrile
8a: Alkene to a less-substituted alkene (regiochemistry change)
The starting material is a trisubstituted alkene and the target is a less-substituted alkene. Route: dehydrate to form an alcohol intermediate (or convert via another path), then use a bulky base (NaOtBu, tBuOH) to favour E2 elimination giving the less-substituted (Hofmann) product. The choice of base controls regioselectivity: NaOtBu favours the less substituted alkene, while smaller bases favour the more substituted (Zaitsev) product.
8b: Alcohol to an alkyne (with an ether group present)
The alcohol cannot react directly with NaC≡CH because an acid-base reaction would occur instead of substitution (the alcohol proton would be removed). Solution: first convert the -OH to a good leaving group (PBr₃/pyr, SOCl₂/pyr, or TsCl/pyr), then react the resulting alkyl halide or tosylate with NaC≡CH via SN2.
8d: Bromocyclohexane to a thioether with retention of configuration
Direct SN2 with NaSCH₃ would give inversion, which is the wrong stereochemistry. Solution: use a double-inversion strategy. First, do a Finkelstein reaction (NaI, DMSO) to swap Br for I with inversion. Then react the iodide with NaSCH₃/DMSO for a second SN2, which inverts again. Two inversions = net retention of the original configuration.
Bonus problem 1: HO-(CH₂)₃-Br → CH₃CH₂O-(CH₂)₃-C≡CH
This molecule has both an -OH and a -Br. The strategy uses selective reactivity:
Treat with NaH to deprotonate the alcohol, forming an alkoxide
The alkoxide reacts intramolecularly or is then treated with CH₃CH₂Br (ethyl bromide) to form the ether via SN2
The remaining bromide end is then treated with NaC≡CH to install the terminal alkyne via SN2
Bonus problem 3: Cyclopentane → cyclopentene oxide (epoxide)
Route: radical bromination (Br₂, hv) to give bromocyclopentane, then E2 elimination (NaOH) to give cyclopentene, then epoxidation with mCPBA to give the cyclopentene oxide.
Bonus problem 4: Butyl bromide → an aldehyde
The key reaction is ozonolysis. Route: SN2 with NaC≡CH to extend the carbon chain and install a triple bond, then partial reduction (H₂/Lindlar catalyst or Na/NH₃) to an alkene, then ozonolysis (1. O₃, 2. Zn) to cleave the double bond and give the aldehyde.
Students often try to react an alcohol directly with a nucleophile like NaC≡CH without first converting the -OH to a leaving group. The problem is that NaC≡CH is a strong base, so it will deprotonate the alcohol (acid-base reaction) rather than performing substitution. You must convert -OH to -Br, -Cl, -I, or -OTs first.
A frequent mistake is forgetting that SN2 inverts stereochemistry. If your target requires retention of configuration at the reacting carbon, a single SN2 step gives the wrong answer. You need a double-inversion strategy (two sequential SN2 reactions).
Students sometimes design routes using SN1 or E1 on primary substrates, or SN2 on tertiary substrates. Always check that your chosen mechanism is compatible with the substrate class.
When asked to make a synthesis "more efficient," students sometimes add steps rather than looking for a single reaction that achieves the same overall transformation. Efficiency means fewer steps, not more reagents per step.
⚠️ Multi-step synthesis problems are high-value exam questions. Expect at least one problem asking you to propose a 2-3 step route from a given starting material to a target.
⚠️ The four-question framework is your lifeline when you feel stuck. Practice using it on every synthesis problem until it becomes automatic.
⚠️ Leaving group installation (converting -OH to -OTs, -Br, or -Cl) is a step students forget. If your starting material has an -OH and your target requires substitution or elimination, you almost certainly need this step.
⚠️ Stereochemistry in synthesis problems is commonly tested. Know when SN2 inverts and when you need double inversion for net retention.
⚠️ Questions about synthetic efficiency ("how could you do this in fewer steps?") test whether you can see a direct route that bypasses an unnecessary intermediate.
Real-world connection: The retrosynthetic approach taught here is precisely what medicinal chemists use when designing routes to drug candidates. The vildagliptin example in this worksheet is a real pharmaceutical case study.
True or false: You can react an alcohol directly with NaCN via SN2 to install a nitrile. → False. You must first convert -OH to a leaving group.
Fill in the blank: Two sequential SN2 reactions on the same carbon give net ___ of configuration. → Retention.
True or false: TsCl/pyridine converts an alcohol to a tosylate, which is a good leaving group for SN2. → True.
Fill in the blank: To make a synthesis more efficient, look for a single reaction that achieves the same overall ___ as the multi-step route. → Transformation.
True or false: In retrosynthetic analysis, you work forward from the starting material. → False. You work backward from the target.
Q: Propose a two-step synthesis to convert an alkene into an alkyl bromide with Markovnikov regiochemistry. Then explain how to do it in one step.
A: Two steps: (1) acid-catalysed hydration (H₃O⁺) to give the Markovnikov alcohol, (2) PBr₃/pyridine to convert -OH to -Br. One step: direct addition of HBr to the alkene gives the Markovnikov bromide.
Q: You need to convert (R)-1-bromocyclohexane to (R)-1-(methylthio)cyclohexane. Direct SN2 with NaSCH₃ gives the wrong stereochemistry. How do you fix this?
A: Use double inversion. Step 1: NaI/DMSO (Finkelstein, SN2, inverts to S). Step 2: NaSCH₃/DMSO (SN2, inverts back to R). Two inversions give net retention.
Q: Why can you not treat a benzylic alcohol directly with sodium acetylide (NaC≡CH) to form a C-C bond?
A: NaC≡CH is a very strong base (conjugate acid pKa ≈ 25). It would deprotonate the -OH (pKa ≈ 16) in an acid-base reaction rather than acting as a nucleophile. You must first convert -OH to a leaving group (e.g. -OTs, -Br) and then treat with NaC≡CH.
Q: Propose a synthesis of cyclopentene oxide (an epoxide) from cyclopentane.
A: Step 1: radical bromination (Br₂, hv) to give bromocyclopentane. Step 2: E2 elimination (NaOH) to give cyclopentene. Step 3: epoxidation (mCPBA) to give cyclopentene oxide.
Q: Starting from 1-bromobutane, propose a route to pentanal (a five-carbon aldehyde).
A: Step 1: SN2 with NaC≡CH to give 1-hexyne (extends the chain by two carbons, forms a C-C bond). Step 2: partial reduction (H₂/Lindlar catalyst) to give cis-1-hexene. Step 3: ozonolysis (1. O₃, 2. Zn) to cleave the double bond and give the aldehyde. The key insight is that the alkynide SN2 step builds the carbon skeleton.
Multi-step synthesis brings together nearly everything from CHEM 212: substitution and elimination mechanisms, alkene and alkyne reactions, alcohol chemistry, and stereochemistry. If any of those areas feel weak, revisiting them will directly improve your synthesis problem-solving.
The retrosynthetic thinking introduced here carries forward into carbonyl chemistry (aldol reactions, Grignard reactions, Wittig reactions), where C-C bond formation becomes the central theme. Mastering the alkynide-based approach now gives you a template for how C-C bond-forming reactions work in general.
Synthetic efficiency connects to green chemistry principles covered in more advanced courses, where minimising steps, waste, and hazardous reagents is a design goal.
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